Corneal subepithelial opacity (haze) inhibitor

ABSTRACT

The present invention relates to a corneal subepithelial opacity (haze) inhibitor comprising as the active ingredient N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the formula:                    
     or a pharmaceutically acceptable salt thereof, is useful for the prevention or treatment of corneal subepithelial opacity (haze) caused by a wound during the operation of refractive surgery such as keratectomy and radial keratotomy, and an external wound.

This is a 371 of PCT/JP97/03371 filed Sept. 24, 1997.

FIELD OF THE INVENTION

The present invention relates to a corneal subepithelial opacity (haze)inhibitor which comprises as the active ingredientN-(3,4-dimethoxycinnamoyl)anthranilic acid (generic name: Tranilast)represented by the formula:

or a pharmaceutically acceptable salt thereof.

More particularly, the present invention relates to an inhibitor ofcorneal subepithelial opacity (haze) caused by an injury to the cornea,which inhibitor comprises as the active ingredient Tranilast or apharmaceutically acceptable salt thereof.

In the present invention, examples of an injury to the cornea include, awound occuring during refractive surgery such as keratectomy and radialkeratotomy, an external wound, other physical injuries to the cornea andthe like.

BACKGROUND OF THE INVENTION

In the ophthalmic field, refractive surgery such as keratectomy andradial keratotomy has recently received public attention. The surgicaltreatment to correct vision is extremely useful in that permanent visioncorrection can be realized in comparison with conventional correctionmethods using compensating lenses such as eye glasses and contactlenses.

Radial keratotomy (RK) is a surgical treatment which involves theplacement of radial incisions extending outwardly from the center of thecornea with a surgical knife. In general, the number of incision linesis in the range of 4-12 and the depth of the cutting is about 90 to 95%of the corneal thickness. However, when performing this procedure, it isvery difficult to place the cuts uniformly. Corneal degeneration afterthe surgery has become a problem. Accordingly, to solve the aboveproblems found in keratotomy using a surgical knife, keratectomy using alaser was designed.

Keratectomy using an excimer laser can be divided into photo refractivekeratectomy (PRK) and phototherapeutic keratectomy (PTK). As an exampleof keratectomy for either procedure, optical keratectomy using anultraviolet laser having a wavelength about 193 nm can be illustrated.Hundreds of thousands of patients have already undergone excimer lasertreatment all over the world. In the United States of America, thisprocedure for curing myopia received FDA approval in October of 1995.Photorefractive keratectomy is employed for curing or improvingparopsia, for example, correcting ametropia such as myopia, hyperopiaand astigmatism. Phototherapeutic keratectomy is useful for treatingopacity regions in the corneal surface associated with cornealdegeneration etc.

However, because these surgical methods involve incision or excision ofthe cornea, in almost all cases corneal subepithelial opacity (haze)will occur at the site of incision or laser application during thewound-healing stage. Especially, because keratectomy involves removal ofthe central corneal epithelium, there is a serious problem that cornealsubepithelial opacity (haze) after the surgery leads to visualdysfunction such as lower vision, glare and regression. However, themechanism of corneal subepithelial opacity (haze) has not yet beenclearly elucidated. In general, corneal subepithelial opacity (haze) isusually transitory. Namely, corneal subepithelial opacity (haze) is notobserved immediately after the surgery and occurs from 2 weeks to 1month after the surgery, i.e., the time that the corneal epithelium hasnearly rehealed. Subsequently, the opacity peaks in 2-3 months after thesurgery and disappears generally at about 6 months to 1 year after thesurgery. Occasionally, the cornea is not completely cured and theopacity remains.

At the present time, on the hypothesis that collagen accumulation playsmore than a small part in corneal subepithelial opacity (haze) afterexcimer laser application, eye drops containing a steroid which hasinhibitory activities on fibroblast cell proliferation and collagenaccumulation and which is used for the treatment of keloid etc., havebeen used as therapeutic agents for curing corneal subepithelial opacity(haze). However, it has been reported that steroids delay rehealing ofthe corneal epithelium because of uncertain effects and that sideeffects such as glaucoma occur occasionally. Furthermore, it has beenreported that instillation on the eyes of fluorouracil, an anticancermedicine, and heparin, an anticoagulant, had no therapeutic effect.Thus, corneal subepithelial opacity (haze) occurs in the eye, which isdistinctive and is greatly different from the other organs and tissues.Therefore, corneal subepithelial opacity (haze) differs from diseasesoccurring in other organs and as such therapeutic agents capable ofeffectively treating diseases which result in cell proliferation orcollagen accumulation do not show favorable effects on cornealsubepithelial opacity (haze). Hence, satisfactory corneal subepithelialopacity (haze) inhibitors have not yet been developed.

Accordingly, development of inhibitors of corneal subepithelial opacity(haze) caused by an injury to the cornea has been desired foraccelerating the healing of a wound such as occurs after keratectomyusing an excimer laser etc. or radial keratotomy, or of external woundor other physical injury and for improving visual dysfunction such aslower vision.

Tranilast has been widely used as an internal medicine or in eye dropsfor the treatment of allergic disorders such as bronchial asthma,allergic rhinitis, atopic dermatitis and allergic conjunctivitis, andcutaneous disorders such as keloid and hypertrophic scar. For example,it has been known that Tranilast has inhibitory activities on chemicalmediator release caused by an allergic reaction, excessive collagenaccumulation by fibroblast cells in cutaneous tissues and excessiveproliferation of smooth muscle cells in coronary artery vessels.

However, it is not known that Tranilast suppresses corneal subepithelialopacity (haze) such as caused by an injury to the cornea.

SUMMARY OF THE INVENTION

The present invention relates to a corneal subepithelial opacity (haze)inhibitor which comprises as the active ingredientN-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the formula:

or a pharmaceutically acceptable salt thereof.

The present invention relates to a method for the prevention ortreatment of corneal subepithelial opacity (haze) which comprisesadministering N-(3,4-dimethoxycinnamoyl)-anthranilic acid represented bythe above formula (I) or a pharmaceutically acceptable salt thereof.

The present invention relates to a use ofN-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the aboveformula (I) or a pharmaceutically acceptable salt thereof for themanufacture of a pharmaceutical composition for the prevention ortreatment of corneal subepithelial opacity (haze)

Furthermore, the present invention relates to a use ofN-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the aboveformula (I) or a pharmaceutically acceptable salt thereof as a cornealsubepithelial opacity (haze) inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating results from the Example of in vivo testfor suppressing corneal subepithelial opacity (haze) using rabbits. Theaxis of the ordinates shows haze score, and the axis of the abscissasshows time after excimer laser radiation (weeks). The symbols —▪—, ——,and —♦— in the graph show the control group, Tranilast group and steroidgroup, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have extensively studied to find compounds whichhave an inhibitory activity on corneal subepithelial opacity (haze)caused by an injury to the cornea. As a result, it was found thatTranilast has a marked inhibitory effect on corneal subepithelialopacity (haze) after excimer laser keratectomy, and is extremely usefulas a corneal subepithelial opacity (haze) inhibitor, thereby forming thebasis of the present invention.

Tranilast was instilled on rabbit eyes radiated with an excimer laser,and the degree of corneal subepithelial opacity (haze) at 2-13 weeksafter the radiation was observed. As a result, the present inventorsconfirmed that corneal subepithelial opacity (haze) in the group treatedwith Tranilast had been significantly suppressed in comparison with thatin the control group not treated with Tranilast.

Thus it has been shown that Tranilast has an extremely excellentinhibitory effect on corneal subepithelial opacity (haze) associatedwith keratectomy, and therefor, is a useful compound as a cornealsubepithelial opacity (haze) inhibitor.

Therefore, pharmaceutical compositions which are useful as a cornealsubepithelial opacity (haze) inhibitor can be prepared by comprising asthe active ingredient Tranilast or a pharmaceutically acceptable saltthereof.

Various methods for the preparation of Tranilast and salts thereof areknown (Japanese Patent Application Publication (kokoku) No.Sho.56-40710;ibid. No.Sho.57-36905; ibid. No.Sho. 58-17186; ibid. No.Sho.58-48545;ibid. No.Sho.58-55138; ibid. No.Sho.58-55139; ibid. No.Hei.01-28013;ibid. No.Hei.01-50219; ibid. No.Hei.03-37539 etc.). For example,Tranilast and pharmaceutically acceptable salts thereof can be preparedby allowing a reactive functional derivative such as an acid halide oran acid anhydride of 3,4-dimethoxycinnamic acid represented by theformula:

to react with anthranilic acid represented by the formula:

in the usual way, and if desired, converting the resulting compound intoa salt thereof.

As examples of pharmaceutically acceptable salts of Tranilast, saltswith inorganic bases such as a sodium salt and a potassium salt, saltsformed with organic amines such as morpholine, piperazine andpyrrolidine and salts formed with amino acids can be illustrated.

The pharmaceutical compositions of the present invention can be employedduring treatment, by oral administration, but topical application witheye drops, eye ointments or the like is preferred.

For example, eye drops of the present invention can be formulated bydissolving Tranilast or a pharmaceutically acceptable salt together witha basic compound with heating in sterilized water in which a surfaceactive agent is dissolved, adding polyvinylpyrrolidone, optionallyadding appropriate pharmaceutical additives such as a preservative, astabilizing agent, a buffer, an isotonicity, an antioxidant and aviscosity improver, and dissolving completely.

Eye ointments of the present invention can be prepared by employing abase material generally used in eye ointments.

When the pharmaceutical compositions of the present invention areemployed in practical treatment, the dosage of Tranilast or apharmaceutically acceptable salt thereof as the active ingredient isappropriately decided based on the age, degree of symptoms and treatmentetc. of each patient and may be fixed within the concentration at whichmedical value is attained.

For example, eye drops, containing preferably 0.001-2 weight %Tranilast, can be instilled 1 to several times per day and applied 1 toseveral droplets per time.

The dose of Tranilast or a pharmaceutically acceptable salt thereof canbe appropriately increased or decreased depending on the type ofdiseases, and degree of symptoms of each patient to be treated and thetherapeutic value.

The present invention is further illustrated in more detail by way ofthe following Example.

Example

In vivo experiment for suppressing corneal subepithelial opacity (haze)

An excimer laser was radiated to both eyes of colored rabbits (Dutch) of22—22 weeks age under the following condition. After the radiation, therabbits were divided into 3 groups (n=7). Each group was respectivelyinstilled with eye drops containing 0.5% Tranilast (Tranilast group),0.1% betamethasone sodium phosphate (steroid group) or a base materiel(control group) 4 times per day, 50 μl per time for 13 consecutiveweeks. The efficacy of suppressing corneal subepithelial opacity (haze)was ophthalmoscopically evaluated according to the followingFantes'classification.

Excimer laser-radiating condition

Application of excimer laser: MINI-EXCIMER COMPAK-200 (LASER SIGHT)

Radiation energy: 0.90 mJ/pulse

Frequency: 100 Hz

Beam spot: 5.5 mm

Ablation depth: 64.89 μm

Fantes' classification

(Grade) (Slit lamp biomicroscopic findings on opacity) 0 Normal 0.5Possible to observe opacity under indirect light 1 Possible to observeopacity under direct light 2 Possible to observe iris in detail 3Difficult to observe iris in detail 4 Impossible to observe iris indetail

The results are shown in FIG. 1. The Tranilast group had a lowerdecrease haze score compared with the control group. Specially, T testshowed that haze scores at 3, 5, 6, 7, 8, 9, 10, 11, 12 and 13 daysafter the surgery were significantly decreased. Accordingly, it wasshown that Tranilast had a marked inhibitory effect on cornealsubepithelial opacity (haze) after excimer laser treatment. On the otherhand, in the steroid group, a decreased haze score was not observedrelative to the control group and corneal subepithelial opacity (haze)was not improved.

Industrial Applicability

A pharmaceutical composition comprising as the active ingredientTranilast has marked inhibitory effect on corneal subepithelial opacity(haze), and is extremely suitable as a corneal subepithelial opacity(haze) inhibitor.

What is claimed is:
 1. A method for the prevention or treatment ofcorneal subepithelial opacity which comprises administeringN-(3,4-dimethoxycinnamoyl)anthranilic acid represented by the formula:

or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein said N-(3,4 dimethoxycinnamoyl) anthranilic acid orpharmaceutically acceptable salt thereof is administered in the form ofeye drops.
 3. The method of claim 1, wherein said N-(3,4dimethoxycinnamoyl) anthranilic acid or pharmaceutically acceptable saltthereof is administered in the form of an eye ointment.
 4. The method ofclaim 1, wherein said N-(3,4 dimethoxycinnamoyl) anthranilic acid orpharmaceutically acceptable salt thereof is administered to the eyeafter eye surgery.
 5. The method of claim 4, wherein said surgery is akeratectomy.
 6. The method of claim 5, wherein said keratectomy is doneby excimer laser.